Combinations of agents which give enhanced anti-inflammatory activity

ABSTRACT

This disclosure describes compatible additive anti-inflammatory compositions comprising certain novel anti-arthritic agents and the known non-steroidal anti-inflammatory agents.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of my copending application Ser. No.121,851, filed Feb. 15, 1980, now abandoned.

BRIEF SUMMARY OF THE INVENTION

This invention relates to new and useful combinations of non-steroidalanti-inflammatory agents and certain anti-arthritic (and alsoanti-inflammatory) agents and their tautomeric forms which may berepresented by the following structural formulae: ##STR1## wherein X isoxo (═O) or imino (═NH) and ARYL is 2-thienyl, 3-thienyl, or a moiety ofthe formula: ##STR2## wherein R is hydrogen or fluoro with the provisothat R may not be ortho-fluoro when X is imino. Also included within thepurview of the present invention are the pharmacologically acceptablecationic salts of the above-defined anti-arthritic agents when X is oxo.Such useful pharmaceutically acceptable salts are those withpharmacologically acceptable metal cations. Preferred metal cations arethose derived from the alkali metals, e.g. lithium, sodium andpotassium, and from the alkaline earth metals, e.g. magnesium andcalcium, although cationic forms of other metals, e.g. aluminum, zinc,iron and in particular copper, are within the scope of the invention.

The non-steroidal anti-inflammatory agents operable in the novelcompositions of the present invention are those which are prostaglandinsynthetase inhibitors and include the following:

ASPIRIN®; 2-(acetyloxy)benzoic acid.

INDOMETHACIN®; 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-aceticacid.

PHENYLBUTAZONE®; 4-butyl-1,2-diphenyl-3,5-pyrazolidenedione.

FENBUFEN®; γ-oxo-(1,1'-biphenyl)-4-butanoic acid.

ALCOFENAC®; 3-chloro-4-(2-propenyloxy)-benzeneacetic acid.

AZAPROPAZONE®;5-(dimethylamino)-9-methyl-2-propyl-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione.

DECLOFENAC® SODIUM; sodium 2-[(2,6-dichlorophenyl)amino]benzeneacetate.

FENCLOZIC ACID®; 2-(4-chlorophenyl)-4-thiazoleacetic acid.

FENOPROFEN®; α-methyl-3-phenoxybenzeneacetic acid.

FLUPROFEN®; 3'-fluoro-α-methyl-(1,1'biphenyl)-4-acetic acid.

FLUFENAMIC ACID®; 2-[3-(trifluoromethyl)phenyl]aminobenzoic acid.

FLURBIPROFEN®; 2-fluoro-α-methyl-(1,1'-biphenyl)-4-acetic acid.

IBUPROFEN®; α-methyl-4-(2-methylpropyl)-benzeneacetic acid.

IBUFENAC®; 4-(2-methylpropyl)-benzeneacetic acid.

ISOXICAN®;4-hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl)-2H-1,2-benzothiazine-3-carboxamide,1,1-dioxide.

KETOPROFEN®; 3-benzoyl-α-methyl-benzeneacetic acid.

FLUFENISAL®; 4-(acetyloxy)-4'-fluoro-(1,1'-biphenyl)-3-carboxylic acid.

SULINDAC®;5-fluoro-2-methyl-1-[4-(methylsulfinyl)phenyl]methylene-1H-indene-3-aceticacid.

METIAZINIC ACID®; 10-methyl-10H-phenothiazine-2-acetic acid.

NAPROXEN®; 5-methoxy-α-methyl-2-naphthaleneacetic acid.

OXYPHENBUTAZONE®;4-butyl-1-(p-hydroxyphenyl)-2-phenyl-3,5-pyrazolidinedione.

PIRPROFEN®;3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-α-methyl-benzeneacetic acid.

TOLEMETIN®; 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid.

CICLOPROFEN®; α-methyl-9H-fluorene-2-acetic acid.

CLONIXIN®; 2-[(3-chloro-2-methylphenyl)amino]-3-pyridinecarboxylic acid.

KETOPHENYLBUTAZONE®; 4-(3-oxobutyl)-1,2-diphenyl-3,5-pyrazolidinedione.

FUROBUFEN®; γ-oxo-2-dibenzofuranbutanoic acid.

INDOPROFEN®;4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-α-methyl-benzeneacetic acid.

CLIPROFEN®; 3-chloro-α-methyl-4-(2-thienylcarbonyl)benzeneacetic acid.

DIFLUNISAL®; 5-(2,4-difluorophenyl)salicylic acid.

FENCLORAC®; α,m-dichloro-p-cyclohexylphenylacetic acid.

FENOPROFEN®CALCIUM; calciumα-methyl-3-phenoxybenzeneacetate.

MECLOFENAMIC ACID®; N-(2,6-dichloro-m-tolyl)anthranilic acid.

OXAPROZIN®; 4,5-diphenyl-2-oxazolepropionic acid.

SUPROFEN®; α-methyl-4-(2-thienylcarbonyl)benzeneacetic acid.

PIROXICAN®;4-hydroxy-2-methyl-N-2-pyridimyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.

MECLOMEN®; N-(2,6-dichloro-m-tolyl)anthranilic acid, monosodium salt.

DETAILED DESCRIPTION OF THE INVENTION

The generally used non-steroidal anti-inflammatory agents operable inthe novel compositions of the present invention exhibit the phenomenonknown as drug interference or drug antagonism. That is, theanti-inflammatory effect of one drug may interfere with theanti-inflammatory effects of the second drug of the combination. As aresult the activity of the combination of the two drugs will neverattain the algebraic sum of the individual actions. It has now beendiscovered that the combination of an anti-inflammatory (antiarthritic)agent as hereinabove defined on page 1 and a known non-steroidalanti-inflammatory agent unexpectedly produces a true additiveanti-inflammatory effect.

A distinct advantage of the present invention lies in the wide range inwhich the anti-inflammatory agents may be employed and still retainadditivity. For example, the proportion of the hereinabove definedanti-arthritic agent to the non-steroidal anti-inflammatory agent mayrange from 100:1 to 1:100 parts by weight although the preferred rangeis not quite so wide and varies from 5:1 to 1:5 parts by weight. Thenovel additive compositions of the present invention have thus beenfound to be highly useful for amelio-rating inflammation and inhibitingjoint deterioration in mammals when administered in amounts ranging fromabout one milligram to about 250 mg. per kilogram of body weight perday. A preferred dosage regimen for optimum results would be from about5 mg. to about 100 mg. per kilogram of body weight per day, and suchdosage units are employed that a total of from about 0.35 gram to about7.0 grams of the additive compositions for a subject of about 70 kg. ofbody weight are administered in a 24 hour period. This dosage regimenmay be adjusted to provide the optimum therapeutic response. Forexample, several divided doses may be administered daily or the dose maybe proportionally reduced as indicated by the exigencies of thetherapeutic situation. A decided practical advantage of this inventionis that the novel compositions may be administered in any convenientmanner such as by the oral, intravenous, intramuscular, topical,intra-articular or subcutaneous routes.

Compositions according to the present invention having the desiredclarity, stability and adaptability for parenteral and intra-articularuse are obtained by dissolving from 0.10% to 10.0% by weight of thecombination in a vehicle consisting of a polyhydric aliphatic alcohol ormixtures thereof. Expecially satisfactory are glycerin, propyleneglycol, and polyethylene glycols. The polyethylene glycols consist of amixture of non-volatile, normally liquid, polyethylene glycols which aresoluble in both water and organic liquids and which have molecularweights of from about 200 to 1500. Although the amount of thecombination dissolved in the above vehicle may vary from 0.10 to 10.0%by weight, it is preferred that the amount employed be from about 3.0 toabout 9.0% by weight. Although various mixtures of the arorementionednon-volatile polyethylene glycols may be employed, it is preferred touse a mixture having an average molecular weight of from about 200 toabout 400.

In addition to the active compositions, the parenteral solutions mayalso contain various preservatives which may be used to preventbacterial and fungal contamination. The preservatives which may be usedfor these purposes are, for example, myristyl-gamma-picolinium chloride,phenyl mercuric nitrate, benzalkonium chloride, phenethyl alcohol,p-chlorophenyl-α-glycerol ether, methyl and propyl parabens, andthimerosal. As a practical matter it is also convenient to employantioxidants. Suitable antioxidants include, for example, sodiumbisulfite, sodium metabisulfite, and sodium formaldehyde sulfoxylate.Generally, from about 0.05 to about 0.2% concentrations of antioxidantare employed.

For intramuscular injection, the preferred concentration of activecomposition is 0.25 to 0.05 mg./ml. of the finished compositions. Theyare equally adapted to intravenous administration when diluted withwater or diluents employed in intravenous therapy such as isotonicglucose in appropriate quantities. For intravenous use, initialconcentrations down to about 0.05 to 0.25 mg./ml. of active compound aresatisfactory. For intra-articular use for large joints such as the knee,from about two to about 20 mg. per joint per week may be used, withproportionally smaller doses for smaller joints.

The additive combinations of the present invention may be orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or they may be enclosed in hard or soft shell gelatincapsules, or they may be compressed into tablets, or they may beincorporated directly with the food of the diet. For oral therapeuticadministration, the compositions may be incorporated with excipients andused in the form of tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparation shouldcontain at least 0.1% of active ingredients. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2% to about 60% of the weight of the unit.The amount of active ingredients in such therapeutically usefulcompositions is such that a suitable dosage will be obtained. Preferredcompositions or preparations according to the present invention areprepared so that an oral dosage unit form contains between about 50 and250 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such as dicalcium phosphate; a disintegratingagent such as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit. For instance, tablets, pills or capsules may becoated with shellac, sugar or both. A syrup or elixir may contain theactive compounds, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and flavoring such as cherry ororange flavor. Of course, any material used in preparing any dosage unitform should be pharmaceutically pure and substantially non-toxic in theamounts employed.

The anti-inflammatory activity of the novel additive compositions of thepresent invention was demonstrated in the adjuvant induced arthritistest in the rat as follows. Groups of three Royal Hart, Wistar strainrats, weighing 200±10 g. each were injected intradermally in the righthind paw with Freund's adjuvant (dried human tubercle bacilli in amineral oil vehicle) at a dose of 2 mg./kg. of body weight. Testcompositions were administered orally in a 1.5% starch vehicle atvarious doses once daily on days 0 through 13 post challenge. Controlrats were treated in a similar manner, but given only starch vehicle. Onthe 14th, 21st, 28th and 35th days post challenge the diameter of theinjected paw (primary lesion) was measured by micrometer caliper. Thevolume of inflamed paws were estimated from these measurements and theresults are expressed as percent inhibition of swelling as compared tocontrols. At the same time, the other inflamed sites, such as ears, pawsand tail (secondary lesions) were observed and each rat was graded as todegree of inflammation and swelling present. The grading is based on ascale of 0 to 24, where 0 represents a complete absence of inducedarthritic modules and 24 represents the maximum degree of inflammation.The mean grade for each treated group is calculated and the effects ofeach test compound are expressed as percent inhibition of the controlgrade. The following Tables I-V record the results of tests conductedwith the compositions of this invention and conventionalanti-inflammatory agents both separately and in combination. All testswere replicated several times. Each treatment group represents a totalof 18 rats. Each challenged control group comprised 36 rats and eachunchallenged control group was 9 rats.

                  TABLE I                                                         ______________________________________                                        The Effect of Combining Benzoylacetonitrile and Indomethacin in               the Treatment of Adjuvant Arthritis                                           Drug Dose                                                                     (mg./kg.) Body Weight                                                                              Primary     Secondary                                           In-    Gain       Lesions   Lesions                                    Benzoyl-                                                                             do-    in Grams   (% Inhibition)                                                                          (% Inhibition)                             aceto- meth-  Day        Day       Day                                        nitrile                                                                              acin   14     21    14    21    14    21                               ______________________________________                                        Normal Rats                                                                             83     111     --    --    --    --                                 Adjuvant                                                                      Controls  40     29      0     0     0     0                                  100    --     56*    79*   55*   54*   76*   56*                              50     --     58*    62*   60*   45*   66*   43*                              25     --     57*    57*   36*   24    50*   17                               --     1.0    76*    70*   57*   24    48*   27                               --     0.5    61*    51*   41*   8     11    3                                --      0.25  43     46    44*   19    25    22                               100    1.0    70*    87*   86*   76*   78*   69*                              50     0.5    63*    89*   77*   74*   75*   66*                              25      0.25  67*    74*   62*   50*   59*   41*                              ______________________________________                                         *Significantly greater than adjuvant controls. p = <.05 by t test        

                  TABLE II                                                        ______________________________________                                        The Effect of Combining Benzimidoylacetonitrile and                           Indomethacin in the Treatment of Adjuvant Arthritis                           Drug Dose                                                                     (mg./kg.) Body Weight                                                                              Primary     Secondary                                           In-    Gain       Lesions   Lesions                                    Benzimi-                                                                             do-    in Grams   (% Inhibition)                                                                          (% Inhibition)                             doylace-                                                                             meth-  Day        Day       Day                                        tonitrile                                                                            acin   14     21    14    21    14    21                               ______________________________________                                        Normal Rats                                                                             123    148     --    --    --    --                                 Adjuvant                                                                      Controls  47     27      0     0     0     0                                  100    --     70*    88*   68*   55*   75*   34*                              50     --     77*    80*   68*   58*   70*   43*                              25     --     72*    66*   56*   33*   63*   24*                              --     1.0    92*    84*   63*   27    54*   30*                              --     0.5    71*    57*   50*   8     32*   10                               --      0.25  59     45    29*   0     22    3                                100    1.0    80*    104*  90*   83*   72*   63*                              50     0.5    76*    83*   82*   68*   69*   48*                              25      0.25  82*    74*   62*   34*   45*   18                               ______________________________________                                         *Significantly greater than adjuvant controls. p = <.05 by t test.       

                                      TABLE III                                   __________________________________________________________________________    The Effect of Combining Benzoylacetonitrile and Aspirin in the Treatment      of Adjuvant Arthritis                                                                       Body Weight Gain                                                                          Primary Lesions                                                                           Secondary Lesions                                     In Grams    (% Inhibition)                                                                            (% Inhibition)                          Drug Dose (mg./kg.)                                                                         Day         Day         Day                                     Benzoylacetonitrile                                                                     Aspirin                                                                           14 21 28 35 14 21 28 35 14 21 28 35                             __________________________________________________________________________    Normal Rats   90 144                                                                              -- -- -- -- -- -- -- -- -- --                             Adjuvant Control                                                                            24 16 22 40 0  0  0  0  0  0  0  0                              25        --  52*                                                                              52*                                                                              75*                                                                              86*                                                                              60*                                                                              36*                                                                              11 4  70*                                                                              40*                                                                              20*                                                                              38*                            12.5      --  57*                                                                              53*                                                                              55*                                                                              81*                                                                              44*                                                                              16*                                                                              10 6  45*                                                                              17*                                                                              25*                                                                              22*                            --        100 45*                                                                              42*                                                                              44*                                                                              48 32*                                                                              8  1  5  14 28*                                                                              25*                                                                              24*                            --         50 19 7  11 32 21*                                                                              0  0  0  27*                                                                              12 31*                                                                              21*                            25        100 52*                                                                              60*                                                                              71*                                                                              83*                                                                              68*                                                                              40*                                                                              28*                                                                              37*                                                                              64*                                                                              45*                                                                              45*                                                                              35*                            25         50 49*                                                                              57*                                                                              59*                                                                              81*                                                                              55*                                                                              20*                                                                              16*                                                                              13*                                                                              65*                                                                              30*                                                                              34*                                                                              27*                            12.5      100 54*                                                                              49*                                                                              43 54 56*                                                                              34*                                                                              24*                                                                              37*                                                                              44*                                                                              40*                                                                              40*                                                                              42*                            12.5       50 50*                                                                              43*                                                                              48 82*                                                                              63*                                                                              41*                                                                              25*                                                                              27*                                                                              55*                                                                              43*                                                                              33*                                                                              24*                            __________________________________________________________________________     *Significantly greater than adjuvant controls. p = <.05 by t test        

                                      TABLE IV                                    __________________________________________________________________________    The Effect of Combining (p-Fluorobenzoyl)-acetonitrile or                     β-Amino-2-thiopheneacrylonitrile                                         and Aspirin in the Treatment of Adjuvant Arthritis                                                     Body Weight Gain                                                                          Primary Lesions                                                                            Secondary Lesions           Drug Dose (mg./kg.)      in Grams    (% Inhibition)                                                                             (% Inhibition)              β-Amino-2-thiophene-                                                                (p-Fluorobenzoyl)-                                                                          Day         Day          Day                         acrylonitrile                                                                         acetonitrile Aspirin                                                                           14 21 28 35 14  21 28 35 14  21 28 35                __________________________________________________________________________    Normal Rats              128                                                                              167                                                                              -- -- --  -- -- -- --  -- -- --                Adjuvant Controls        52 50 52 89 0   0  0  0  0   0  0  0                 --         --        100 47 46 57 97 10  2  13 1  1   2  2  4                 --         --        50  45 42 60 93 16* 11 17*                                                                              0  5   10 20 0                 --         50        --  75*                                                                              77*                                                                              93*                                                                              125*                                                                             53* 32*                                                                              27*                                                                              22*                                                                              34* 10 28*                                                                              19                --         25        --  71*                                                                              65 80*                                                                              111*                                                                             30* 17*                                                                              0  6  23* 0  0  7                 --         50        100 75*                                                                              72*                                                                              98*                                                                              141*                                                                             57* 42*                                                                              37*                                                                              43*                                                                              17  17 9  12                --         25        100 69*                                                                              81*                                                                              86*                                                                              116*                                                                             58* 43*                                                                              24*                                                                              28*                                                                              38* 24*                                                                              9  13                --         50        50  77*                                                                              68*                                                                              74*                                                                              100                                                                              54* 24*                                                                              3  14 24* 2  10 14                --         25        50  74*                                                                              75*                                                                              86*                                                                              117*                                                                             40* 24*                                                                              18*                                                                              0  19  1  9  5                 50         --        --  63 66*                                                                              76*                                                                              108*                                                                             16  14 6  1  13  0  4  11                50         --        100 46 54 54 88 40* 23*                                                                              10 0  12  6  0  0                 50         --        50  70*                                                                              96*                                                                              102*                                                                             143*                                                                             58* 35*                                                                              32*                                                                              26 27* 7  10 10                __________________________________________________________________________     *Significantly greater than adjuvant controls. p = <.05 by t test        

                                      TABLE V                                     __________________________________________________________________________    The Effect of Combining Benzoylacetonitrile and Prednisolone                  in the Treatment of Adjuvant Arthritis                                                         Body Weight Gain                                                                         Primary Lesions                                                                         Secondary Lesions                                        in Grams   (% Inhibition)                                                                          (% Inhibition)                          Drug Dose (mg./kg.)                                                                            Day        Day       Day                                     Benzoylacetonitrile                                                                     Prednisolone                                                                         14                                                                              21 28 35 14                                                                              21                                                                              28 35 14                                                                              21                                                                              28 35                               __________________________________________________________________________    Normal Rats      96                                                                              137                                                                              -- -- --                                                                              --                                                                              -- -- --                                                                              --                                                                              -- --                               Adjuvant Controls                                                                              34                                                                              27 32 58 0 0 0  0  0 0 0  0                                25        --     47                                                                              47*                                                                              51*                                                                              69 62*                                                                             38*                                                                             31*                                                                              30*                                                                              62*                                                                             30*                                                                             19 20*                              12.5      --     49                                                                              38 55*                                                                              68 49*                                                                             32*                                                                             25*                                                                              19*                                                                              59*                                                                             43*                                                                             25 26*                              --        10     23                                                                              47 75*                                                                               95*                                                                             57*                                                                             24*                                                                             14 13 55*                                                                             21*                                                                             3  17*                              --         5     22                                                                              26 44 71 63*                                                                             24*                                                                             17*                                                                              11 45*                                                                             16*                                                                             5  20*                              25        10     34                                                                              71*                                                                              94*                                                                              119*                                                                             88*                                                                             65*                                                                             49*                                                                              42*                                                                              72*                                                                             64*                                                                             39*                                                                              35*                              12.5      10     30                                                                              56*                                                                              87*                                                                              118*                                                                             78*                                                                             52*                                                                             28*                                                                              34*                                                                              77*                                                                             33*                                                                             17 15                               25         5     33                                                                              55*                                                                              64*                                                                               91*                                                                             83*                                                                             53*                                                                             36*                                                                              38*                                                                              80*                                                                             40*                                                                             13 19*                              12.5       5     45                                                                              63*                                                                              66*                                                                               83*                                                                             78*                                                                             33*                                                                             22*                                                                              23*                                                                              67*                                                                             13*                                                                             7  10                               __________________________________________________________________________     *Significantly greater than adjuvant controls. p = <.05 by t test        

Adjuvant induced experimental polyarthritis is a specific systemicdisease of the rat which shares interesting similarities with rheumatoidarthritis. Specifically, the histology of the two diseases bears aremarkable resemblance as shown by C. M. Pearson et al., Am. J. Pathol.42, 73 (1963). E. M. Glenn, Am. J. Vet. Res. 27 (116), 339 (1966) hasclassified adjuvant induced polyarthritis as a crippling and permanentdeformity resulting from diffuse connective tissue involvement aroundcertain susceptible joints in the rat. Zahiri et al., Can. Med. Ass. J.101, 269 (1969) have shown that the fusiform swelling of the distaljoints is associated with edema, congestion and synovitis includingpannus formation, all of which precede the ultimate destruction of boneand cartilage. Furthermore, Zahiri et al., indicate that the cartilagedestruction in the joint is due to an invasive pannus which originatesin the marginal synovium and extends across the articular surface toerode it. When non-steroidal, anti-inflammatory agents such asindomethacin inhibit arthritic paw swelling, which is composed ofinflammatory cell infiltrates, they have also been shown to preventjoint and bone deterioration. See S. Wong et al., J. Pharm. & Exptl.Ther. 185, 127 (1973) and G. R. Bobalick et al., Agents & Actions 4, 364(1974). In a similar manner, inhibition of the progress of arthritis inpaws of rats treated with the compounds of this invention also lessensassociated joint deterioration.

The invention will be described in greater detail in conjunction withthe following specific examples.

EXAMPLE 1 Benzoylacetonitrile

The compound benzoylacetonitrile may be prepared as described by Dorsch,et al., J.A.C.S., 54, 2960 (1932).

EXAMPLE 2 (p-Fluorobenzoyl)-acetonitrile

The compound (p-fluorobenzoyl)-acetonitrile may be prepared as describedby Pihl. et al., Reakts, Sposobnost Org. Soedin. Tartu. Gos. Unit.,5(1), 27 (1968).

EXAMPLE 3 (o-Fluorobenzoyl)-acetonitrile

The compound (o-fluorobenzoyl)-acetonitrile may be prpeared as describedby M. Nakanishi, et al., J. Med. Chem., 16(3), 214-219 (1973).

EXAMPLE 4 (m-Fluorobenzoyl)-acetonitrile

The compound (m-fluorobenzoyl)-acetonitrile may be prepared as describedby Pihl, et al., Reakts. Sposobnost Org. Soedin. Tartu. Gos. Unit.,5(1), 27 (1968).

EXAMPLE 5 β-Oxo-2-thiophenepropionitrile

This compound may be prepared as described in U.S. Pat. No. 2,540,982.

EXAMPLE 6 β-Amino-3-thiopheneacrylonitrile

A 500 ml., three-necked flask is equipped with a mechanical stirrer, gasinlet, dry ice condenser, potassium hydroxide drying tube and additionfunnel. A 100 ml. portion of ammonia is condensed into the flask and apellet of sodium is added. When the dark blue colors persists, ferricchloride is added discharging the color to brown. A 3.2 g. portion ofsodium is added and the mixture is allowed to stand for 45 minutes. A5.7 ml. portion of acetonitrile in 10 ml. of tetrahydrofuran is addedand the reaction is stirred for 20 minutes. The reaction is cooled in adry ice-acetone bath and 10.9 g. of 3-thiophenecarbonitrile in 25 ml. oftetrahydrofuran is added. The reaction is stirred in the cold bath for90 minutes and then heated at reflux for 3 hours. A 7.4 g. portion ofammonium chloride is added and the mixture is allowed to evaporateovernight. A 100 ml. portion of water and 100 ml. of chloroform areadded and the mixture is filtered. The aqueous phase is extracted withchloroform, the combined organic solution is washed once with water,dried over magnesium sulfate and filtered through Magnesol. The filtrateis evaporated in vacuo to an orange oil. A 30 ml. portion of benzene isadded and then petroleum ether until the mixture is cloudy. Coolingproduces a precipitate which is collected and recrystallized frombenzene giving the desired product as a solid, mp. 67°-69.5° C.

EXAMPLE 7 β-Oxo-3-thiophenepropionitrile

A 1.2 g. portion of β-amino-3-thiopheneacrylonitrile is added to 10 ml.of 1 N hydrochloric acid. A 40 ml. portion of methanol is added and themixture is stirred for 3 hours. The mixture is evaporated in vacuo to aresidue which is dissolved in 35 ml. of hot methanol and treated withcharcoal. After cooling, petroleum ether is added, the mixture isfiltered and the collected solid is discarded. The filtrate isevaporated and the residue is dissolved in 35 ml. of hot isopropanol andthe insoluble material is filtered and discarded. The filtrate is cooledand the solid is collected giving the desired produce as white plates,mp. 87°-88° C.

EXAMPLE 8 β-Amino-2-thiopheneacrylonitrile

A reaction flask is dried by flaming with a stream of nitrogen passingthrough it.

About 100 ml. of ammonia is condensed in the reaction flask and a smallpiece of sodium is added, giving a blue color. The color is dischargedwith ferric chloride and 2.7 g. of sodium is added. When the blue colordisappears, 4.91 ml. of acetonitrile in 10 ml. of ether is added. Thereaction is cooled in a dry ice-acetone bath and 9.28 g. of2-thiophenecarbonitrile in 25 ml. of tetrahydrofuran is added dropwise.Cooling is continued for 30 minutes, then the ammonia and solvent areallowed to evaporate. A 50 ml. portion of water is added and the mixtureis extracted with methylene chloride. The methylene chloride extractsare dried over sodium sulfate and then passed through Magnesol. Hexanesare added and the filtrate is evaporated on a steam bath to an oil. Theoil is dry column chromatographed on silica gel, eluting with methylenechloride. The fraction containing the desired product is taken up inmethylene chloride, passed through Magnesol and the filtrate isevaporated on a steam bath with the addition of hexanes until an oilcomes out. Cooling and seeding gives the desired product as crystals,mp. 50°-45° C.

EXAMPLE 9 Benzimidoylacetonitrile

The compound benzimidoylacetonitrile may be prepared as described inChemical Abstracts, 62, 10366H (1965). It is also commercially availablefrom Aldrich Chemical Company.

EXAMPLE 10 p-Fluorobenzimidoylacetonitrile

The compound p-fluorobenzimidoylacetonitrile may be prepared asdescribed by Lang, et al., J. Med. Chem., 18, 441 (1975).

EXAMPLE 11 m-Fluorobenzimidoylacetonitrile

A 1.21 g. portion of m-fluorobenzonitrile, 0.52 ml. of acetonitrile, 0.5g. of sodium hydride and 0.1 ml. of t-butanol are added to 25 ml. ofether. The mixture is refluxed on a steam bath for one hour. Methanoland water are added. The layers are separated and the aqueous layer isextracted with two 25 ml. portions of ether. The combined ether layersare dried over sodium sulfate, passed through diatomaceous earth,diluted with hexanes and evaporated on a steam bath. The resulting oilis chromatographed using methylene chloride on silica gel giving 0.52 g.of an oil which crystallizes. This material is taken up in methylenechloride. Hexanes are added and the mixture is evaporated, giving an oilwith crystallizes. This material is recrystallized from carbontetrachloride giving the desired product, mp. 67°-68° C.

EXAMPLE 12 Preparation of 50 ml. Tablets

    ______________________________________                                        Per Tablet                                                                    ______________________________________                                        0.050 g.        Benzoylacetonitrile                                           0.324 g.        Aspirin®                                                  0.080 g.        Lactose                                                       0.010 g.        Corn starch (for mix)                                         0.008 g.        Corn starch (for paste)                                       0.472 g.                                                                      0.002 g.        Magnesium stearate (1%)                                       0.474 g.                                                                      ______________________________________                                    

The benzoylacetonitrile, aspirin, lactose and corn starch (for mix) areblended together. The corn starch (for paste) is suspended in 600 ml. ofwater and heated with stirring to form a paste. This paste is then usedto granulate the mixed powders. Additional water is used if necessary.The wet granules are passed through a No. 8 hand screen and dried at120° F. The dried granules are passed through a No. 16 screen. Themixture is lubricated with 1% magnesium stearate and compressed intotablets.

EXAMPLE 13 Preparation of Oral Syrup

    ______________________________________                                        Ingredient          Amount                                                    ______________________________________                                        (p-Fluorobenzoyl)-acetonitrile                                                                    500        mg.                                            Indomethacin®   100        mg.                                            Sorbitol solution (70% N.F.)                                                                      40         ml.                                            Sodium benzoate     150        mg.                                            Saccharin           10         mg.                                            Red dye             10         mg.                                            Cherry flavor       50         mg.                                            Distilled water qs ad                                                                             100        ml.                                            ______________________________________                                    

The sorbitol solution is added to 40 ml. of distilled water and the(p-fluorobenzoyl)-acetonitrile and indomethacin are suspended therein.The saccharin, sodium benzoate, flavor and dye are added and dissolved.The volume is adjusted to 100 ml. with distilled water. Each ml. ofsyrup contains 5 mg. of (p-fluorobenzoyl)-acetonitrile and one mg. ofindomethacin.

EXAMPLE 14 Preparation of Hard Shell Capsule

    ______________________________________                                        Ingredient           mg./Capsule                                              ______________________________________                                        β-Amino-2-thiopheneacrylonitrile                                                              500                                                      Phenylbutazone®  5                                                        Lactose, Spray dried qs                                                       Magnesium stearate   5                                                        ______________________________________                                    

The components are blended and filled in hard shell capsules.

EXAMPLE 15 Preparation of Parenteral Solution

In a solution of 700 ml. of propylene glycol and 200 ml. of water forinjection is suspended 20.0 grams of benzimidoylacetonitrile and 20.0grams of Naproxen® with stirring. After suspension is complete, the pHis adjusted to 5.5 with hydrochloric acid and the volume is made up to1000 ml. with water for injection. The formulation is sterilized, filledinto 5.0 ml. ampoules each containing 2.0 ml. (representing 40 mg. ofactive ingredients and sealed under nitrogen.

EXAMPLE 16 Preparation of Topical Cream

    ______________________________________                                        Ingredient          Amount                                                    ______________________________________                                        Benzoylacetonitrile 1.0%                                                      Fenbufen            1.0%                                                      Ethoxylated stearyl alcohol                                                                       10.0%                                                     Benzyl alcohol      0.9%                                                      Isopropyl palmitate 5.0%                                                      Glycerin            5.0%                                                      Sorbitol solution (USP)                                                                           5.0%                                                      Lactic acid qs. to pH 4.0-5.0                                                 Water qs. to        100.0%                                                    ______________________________________                                    

The ethoxylated stearyl alcohol and isopropyl palmitate are heated toliquifying temperature. About 95% of the total volume of water is placedin a separate container followed by the glycerin and sorbitol solution.This aqueous mixture is brought to a boil and then cooled to 60°-75° C.The m-fluorobenzimidoylacetonitrile and Fenbufen are added to the waxphase and the mixture is stirred until a clear solution is obtained. Thebenzyl alcohol is added and dissolved in the wax phase while maintainingagitation. Both phases are kept at about the same temperature duringtransfer. The mixture is cooled while agitation is continued. At atemperature of 50°-55° C. the balance of the water is added. The pH isadjusted to 4.0-5.0 with lactic acid. The batch is cooled with minimumagitation until the cream sets in its final form.

EXAMPLE 17 Preparation of Intra-articular Product

    ______________________________________                                        Ingredient           Amount                                                   ______________________________________                                        p-Fluorobenzoylacetonitrile                                                                         2-20 mg.                                                Oxyphenbutazone® 10-20 mg.                                                NaCl (physiological saline)                                                                        0.9%                                                     Benzyl alcohol N.F.  0.9%                                                     Sodium carboxymethylcellulose                                                                       1-5%                                                    pH adjusted to 5.0-7.5                                                        Water for injection qs ad                                                                          100%                                                     ______________________________________                                    

EXAMPLE 18 Preparation of Injectable Depo Suspension

    ______________________________________                                        Ingredient           % W/V                                                    ______________________________________                                        p-Fluorobenzoylacetonitrile                                                                        0.05-5.0                                                 Ketophenylbutazone®                                                                            0.10-8.0                                                 Polysorbate 80 USP   0.2                                                      Polyethylene glycol 4000 USP                                                                       3.0                                                      Sodium chloride USP  0.8                                                      Benzyl alcohol N.F.  0.9                                                      HCl to pH 6-8        qs                                                       Water for injection qs ad                                                                          100.0                                                    ______________________________________                                    

I claim:
 1. An anti-inflammatory composition of matter comprising, inadditive combination, a mixture of 2-(acetyloxy)benzoic acid and anagent of the formula: ##STR3## wherein X is oxo or imino and R ishydrogen or fluoro with the proviso that R may not be ortho-fluoro whenX is imino, in the proportion of the 2-(acetyloxy)benzoic acid to theagent of from 100:1 to 1:100 parts by weight.
 2. A composition accordingto claim 1 wherein X is oxo and R is para-fluoro.
 3. The method ofmeliorating inflammation in a mammal which comprises administering tosaid mammal an effective amount of an anti-inflammatory composition inaccordance with claim
 1. 4. The method of inhibiting progressive jointdeterioration in a mammal which comprises administering to said mammalan effective amount of an anti-inflammatory composition in accordancewith claim
 1. 5. The method of inhibiting the progression of arthritisis a mammal which comprises administering to said mammal an effectiveamount of an anti-inflammatory composition in accordance with claim 1.